Objective The molecular basis for the antithrombin (AT) deficiency and dilated cardiomyopathy (DCM) combined in a Japanese patient was investigated.
Methods We analyzed candidate genes -
SERPINC1 for AT deficiency, and
TNNT2 and
LMNA for DCM. In addition, we examined the characteristics of recombinant mutant AT and evaluated the
LMNA mutation associated with DCM by molecular modeling.
Results Genome sequencing of
SERPINC1 revealed a C-to-A transversion in exon 6 that resulted in a p.Pro439Thr mutation of AT, which was previously reported as a pleiotropic effect type II AT deficiency (AT Budapest5). However, expression experiments with recombinant 439Thr-AT showed normal heparin affinity, slightly reduced secretion, and low specific activity, which suggested that this mutation exhibits an intermediate feature of type I and type II AT deficiencies. In a survey of gene abnormalities causing DCM, we found no causative gene defect in
TNNT2; however, we identified a G-to-C transversion in
LMNA that resulted in a novel p.Asp357His mutation in lamin A/C. This acidic-to-basic residue substitution might have impaired the head-to-tail association of two lamin dimers leading to DCM. Further, we identified both
SERPINC1 and
LMNA mutations in the patient's daughter and son, both of whom had AT deficiency. These data suggested that a p.Pro439Thr mutation in
SERPINC1 and a p.Asp357His mutation in
LMNA might have cosegregated in this family, associated with AT deficiency and DCM, respectively.
Conclusions We identified missense mutations in
SERPINC1 and
LMNA genes to be associated with AT deficiency and DCM, respectively, which might have cosegregated in the family of the patient.
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